Post-Traumatic Stress Disorder (PTSD) is a chronic and disabling condition that can occur in individuals who experience a traumatic event. Given the rising prevalence of PTSD, especially combat related, studies on the search for novel, effective interventions and preclinical models relevant to PTSD are currently a high priority. Poor post-trauma recovery and susceptibility to PTSD is an outcome of impaired resilience and coping to stress. Abnormalities in the stress regulatory systems of the body are also found in PTSD. Neuropeptide Y (NPY) is a major transmitter that is linked to the regulation of stress and anxiety, and has been recognized as a stress resilience factor in humans and rodents. In recent studies, we have reported low cerebrospinal fluid concentrations of NPY in veterans with PTSD. The physiological and therapeutic relevance of NPY to PTSD is of high interest but remains to be investigated. This Merit Review application proposes to investigate NPY in a preclinical rodent model of PTSD to gain physiological and therapeutic relevance of NPY to PTSD. Importantly, therapeutic potential of NPY and novel, brain permeant NPY analogs will also be screened for recovery outcomes following trauma. The rodent model of chronic variable stress (CVS) simulates the unpredictability, chronicity and lack of control of combat- associated trauma and invokes the expression of PTSD-like behaviors/physiology. Importantly, our data has shown a persistent CVS-evoked deficit of NPY in the amygdala (a region dysregulated in individuals with PTSD). The central hypothesis of this application is that deficiency of amygdalar NPY promotes the expression of anxiety, exaggerated fear-memory (re-experiencing), startle (hyperarousal) and sympathetic overdrive; and that supplementation of NPY or peripherally injected NPY analogs will promote resistance/resilience to CVS induced deficits. Three specific aims will investigate these hypotheses: Aim 1 will test the hypothesis that exposure to CVS will lead to delayed and persistent dysregulation of amygdalar NPY system, Aim 2 will test the hypothesis that deficits in amygdalar NPY prior to CVS trauma will exacerbate behavioral and physiological deficits evoked by CVS trauma Aim 3 will test the hypothesis that supplementation of amygdalar NPY or NPY-Y2 antagonists is sufficient to induce resistance/resilience to late- emerging chronic stress-induced behavioral deficits. Collectively, our data will determine the physiologic and potential therapeutic relevance of NPY in PTSD. Relevance: This preclinical study will provide the rationale to proceed with the development of NPY analogs for PTSD pharmacotherapy and as a potential biomarker for predicting trauma outcomes.